Double-edged Sword Role of Iron-loaded Ferritin in Extracellular Vesicles

Our plain-English summary of Double-edged Sword Role of Iron-loaded Ferritin in Extracellular Vesicles, by S. Toyokuni, Y. Kong, H. Zheng, et al (Journal of Cancer Prevention, 2021).

The study

• Authors: S. Toyokuni, Y. Kong, H. Zheng, D. Mi, M. Katabuchi, Y. Motooka, F. Ito
• Journal: Journal of Cancer Prevention
• Published: 2021;26(4):244-249
• Type of article: Review
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Human epidemiological and animal studies have demonstrated that excess iron is a risk for cancer. The responsible mechanisms are: 1) increased intracellular iron catalyzes the Fenton reaction to generate hydroxyl radicals, leading to mutagenic oxidative DNA lesions; 2) iron is necessary for cellular proliferation as cofactors of many enzymes. Thus, iron-excess milieu promotes selecting cellular evolution to ferroptosis-resistance, a major basis for carcinogenesis. Ferritin is a 24-subunit nanocage protein required for iron storage under the regulation of the iron-regulatory protein (IRP)/iron-responsive element (IRE) system. Ferritin is a serum marker, representing total body iron storage. However, how ferritin is secreted extracellularly has been unelucidated. We recently discovered that an exosomal marker CD63 is regulated by the IRP/IRE system and that iron-loaded ferritin is secreted as extracellular vesicles under the guidance of nuclear receptor coactivator 4 (NCOA4). On the other hand, we found that macrophages under asbestos-induced ferroptosis emit ferroptosis-dependent extracellular vesicles (FedEVs), which are received by nearby mesothelial cells, resulting in significant mutagenic DNA damage. Therefore, cells, including macrophages, can share excess iron with other cells, via iron-loaded ferritin packaged in extracellular vesicles as safe non-catalytic iron. However, similar process, such as one involving FedEVs, may cause accumulation of excess iron in other specific cells, which may eventually promote carcinogenesis.

Copyright © 2021 Korean Society of Cancer Prevention.

In plain English

This article was a short review by researchers at Nagoya University, Japan, not a new study. It summarized published work, much of it the authors' own, on how cells store and pass on iron and how this may relate to cancer, including asbestos-induced mesothelioma. The authors described their earlier finding that ferritin, an iron-storage protein, leaves cells loaded with iron inside tiny packets called extracellular vesicles, a process involving the proteins CD63 and NCOA4. They also summarized their earlier reports from 2020 and 2021: macrophages (immune cells) that took up asbestos fibers underwent an iron-dependent cell death called ferroptosis and released vesicles carrying iron-loaded ferritin, which nearby mesothelial cells received, resulting in DNA damage. The review reported no new data, and its main text did not say which asbestos fiber type was used in the summarized macrophage and vesicle work. The authors concluded that cells can share excess iron safely this way, but that a similar process may cause excess iron to build up in certain cells and may eventually promote cancer.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Review article summarizing published laboratory, animal and human research, largely the authors' own earlier work; no new data
• Who was studied: Not applicable: a review with no study population of its own
• Exposure: Asbestos in general, discussed as a cause of mesothelioma through iron and ferroptosis in macrophages. The main text does not name a specific fiber type for the summarized macrophage and vesicle findings, though titles in the reference list mention chrysotile and other fiber types.
• Main results:
  • The authors summarized their own earlier report that the exosome marker CD63 is controlled by the cell's iron-sensing system (IRP/IRE) and that iron-loaded ferritin is released from cells in extracellular vesicles guided by NCOA4. This is a finding from previously published work, not new data in this review.
  • The authors summarized their 2020 report that macrophages create a mutagenic environment for surface mesothelial cells through ferroptosis after taking up asbestos fibers.
  • The authors summarized their 2021 report that macrophages undergoing asbestos-induced ferroptosis release ferroptosis-dependent extracellular vesicles (FedEVs), which nearby mesothelial cells take up, resulting in significant mutagenic DNA damage.
  • In the authors' diagram of this process, the vesicles released by macrophages are shown carrying iron-loaded ferritin.
• The authors' conclusion: The authors concluded that cells, including macrophages, can share excess iron with other cells as safe non-catalytic iron in ferritin packed in extracellular vesicles. They also concluded that a similar process, such as one involving FedEVs, may cause excess iron to accumulate in specific cells and may eventually promote carcinogenesis.

Topics

Medical terms in this study, explained in our Lexicon: Ferritin, Fenton Reaction, Hydroxyl Radical, DNA lesions, Carcinogenesis, Macrophage, Mesothelial Cells.

Related studies

• Ferroptosis-dependent extracellular vesicles from macrophage contribute to asbestos-induced mesothelial carcinogenesis through loading ferritin — F. Ito, K. Kato, et al. (2021)
• Reactive oxygen species a double-edged sword for mesothelioma — S. Benedetti, B. Nuvoli, et al. (2015)
• Plasmatic extracellular vesicle microRNAs in malignant pleural mesothelioma and asbestos-exposed subjects suggest a 2-miRNA signature as potential biomarker of disease — T. Cavalleri, L. Angelici, et al. (2017)
• Extracellular vesicles as biomarkers in malignant pleural mesothelioma: A review — T. Ahmadzada, S. Kao, et al. (2020)
• Diagnostic and Prognostic Utility of the Extracellular Vesicles Subpopulations Present in Pleural Effusion — J. Javadi, A. Görgens, et al. (2021)
• Small and Large Extracellular Vesicles Derived from Pleural Mesothelioma Cell Lines Offer Biomarker Potential — T. Ahmadzada, A. Vijayan, et al. (2023)

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